PML is crucial for neural stem cell differentiation, stress tolerance and mitochondrial integrity.

The tumor suppressor promyelocytic leukemia protein (PML) has important roles in brain development; however, the molecular and cellular pathways regulated by PML in neuronal cells remain largely unknown. To address this issue, we analyzed gene expression changes caused by loss of PML in neural stem cells. Our findings revealed that PML-deficient cells exhibited increased mTOR (mammalian target of rapamycin) pathway activation and protein translation, as well as impaired autophagy and proteasome activity, resulting in increased formation of aggregates and stress-induced death. Loss of PML disrupted mitochondrial integrity, leading to impaired respiration, membrane potential, morphology, and production of increased reactive oxygen species. These mitochondrial defects were caused by diminished PGC-1α expression and PPARγ (peroxisome proliferator-activated receptor gamma) signaling and could be reversed using a PPAR agonist. Together, our results indicate that PML is a critical regulator of neuronal survival and protection from stress. We propose that enhancing PML expression may offer therapeutic benefits in neurological disorders.